Spondyloepiphyseal dysplasia in a Cape Town family: linkage with the gene for type II collagen (COL2A1).

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED.     

Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen

A mild autosomal dominant form of spondyloepiphyseal dysplasia (SED) is present in several generations of a South African family of English stock. This phenotype differs from that of any other previously described. Although type II collagen defects have been found in some families with SED congenita, the phenotype in our family showed discordant segregation with COL2A1 gene associated restriction fragment length polymorphisms (RFLPs), the markers for the structural locus of type II collagen. It is evident that the SED group of disorders is heterogeneous.     

Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint unlinked to COL2A1

Molecular investigations have been undertaken in several separate large South African families with autosomal dominant skeletal dysplasias in which premature degenerative osteoarthropathy of the hip joint was the major manifestation. There are sometimes additional minor changes in the spine and these conditions fall into the general spondyloepiphyseal dysplasia (SED) nosological category. In some kindreds, linkage between phenotype and the type II collagen gene (COL2A1) has been established, while in others there is no linkage. We have now completed molecular linkage investigations in an Afrikaner family named Beukes, in which 47 members in 6 generations have premature osteoarthropathy of the hip joint. A LOD score of minus infinity indicates that this condition is not the result of a defect of the COL2A1 gene. © 1994 Wiley-Liss, Inc.     

Five families with arginine519-cysteine mutation in COL2A1: Evidence for three distinct founders

Arginine519-cysteine mutation in the type II procollagen gene (COL2A1) is known to be associated with mild spondyloepiphyseal dysplasia (SED) and precocious generalized osteoarthritis (OA). Five families have now been identified with this mutation. To determine whether a common founder was responsible for the mutation in these five families, we defined the haplotype of the mutation-bearing chromosome using four restriction fragment length polymorphisms (RFLPs) and the 3′-untranslated region VNTR. Haplotype frequencies were estimated for 69 control samples. Three distinct mutation-bearing haplotypes were identified, with three families sharing a common haplotype. For three distinct haplotypes to have derived from a single founder, three independent recombination events would have had to occur. Thus the arg519 codon appears to represent a possible site of recurrent mutations in COL2A1, an uncommon phenomenon in collagen genes. Hum Mutat 12:172–176, 1998. © 1998 Wiley-Liss, Inc.     

Identification of a locus for a form of spondyloepiphyseal dysplasia on chromosome 15q26.1: exclusion of aggrecan as a candidate gene

We have investigated a family with an autosomal dominant form of spondyloepiphyseal dysplasia (SED) characterised by short stature and severe premature degenerative arthropathy. Previous studies have excluded linkage between this condition and the locus for the type II collagen gene. Here we report the identification of linkage between this disorder and a locus on the long arm of chromosome 15 between markers D15S979 and D15S1004. According to current linkage maps and sequence data, this locus includes that of the aggrecan gene (AGC1). Our linkage data from the SED family show, however, that AGC1 maps to a locus that is proximal to D15S979. This proximal location for AGC1 is further supported by linkage data from a second family with an autosomal recessive form of multiple epiphyseal dysplasia that also maps to the SED locus. In both families AGC1 is therefore excluded as a candidate gene.     

Selective activation of VH3A10+ rheumatoid factor producing B cells by staphylococcal enterotoxin D

Staphylococcal enterotoxin D (SED) is a T cell superantigenwhich selectively targets ß TCRs bearing particularV^ß elements. A second function of SED relates to thepreferential activation of a B cell subset characterized bya high frequency of rheumatoid factor (RF) producing B cells.To define the molecular basis of the SED-induced B cell repertoireshift, we have analyzed Ig heavy chain genes in B cell clonesexpanded after SED stimulation and compared them with B cellclones established in the presence of anti-CD3 stimulated helpercells. Gene segments of the V_H3 family were most frequentlyutilized under both stimulation conditions (42% anti-CD3; 47%SED). Sequence analysis of V_H3 gene segments demonstrated thatthe repertoire of V_H3 elements in B cell clones from SED drivenand anti-CD3 driven cultures were distinct (P=0.01). RF activitywas closely associated with the expression of selected V_H3 elements.B cell clones stimulated with SED preferentially expressed V_H3A10,whereas V_H26 was the gene segment dominantly used in B cellclones expanded with anti-CD3 stimulated helper cells. The usageof J_H and D_H elements was indistinguishable in SED and anti-CD3driven B cell clones, suggesting that SED targets V_H3⁺ B cellsthrough a V_H-specific mechanism. Comparison of the closely relatedsequences of the SED responsive V_H3A10 and the SED non-responsiveV_H26 element suggested a role of a sequence polymorphism inthe CDR2 reminiscent of B cell reactivity to conventional antigens.In contrast to conventional antigens, SED can induce differentiationof a high frequency of naive B cells. Thus, this staphylococcalenterotoxin combines selective activation of T cells with selectiveactivation of B cells and might be able to direct T cell helpto RF producing B cells.     

Associations of light physical activity,moderate-to-vigorous physical activity and sedentary behavior with quality of life in men on androgen deprivation therapy for prostate cancer: a quantile regression analysis

To examine associations of physical activity (PA) and sedentary time (SED) with quality of life (QoL) in men on androgen deprivation therapy (ADT) for prostate cancer. A pooled analysis of 106 men on ADT was conducted. PA and SED were assessed using accelerometers. The Functional Assessment of Cancer Therapy (FACT) was used to assess self-reported QoL. Quantile regression examined the associations of QoL with PA and SED. Total time spent in SED was positively associated with FACT-General at the 50th (p?=?0.010) and 75th percentile (p?=?0.022). SED in?≥?30-min bouts was inversely associated with FACT-General at the 50th  (p?=?0.025) and 75th percentile (p?=?0.029). Breaks in SED were positively associated with physical well-being at the 75th percentile (p?=?0.004). Light-intensity PA was positively associated with FACT-Prostate at the 25th percentile (p?=?0.020). SED and PA were associated with QoL outcomes, but time in each varied across men reporting the poorest QoL compared to those in the highest QoL distributions.

     

Mutational analysis of the binding of staphylococcal enterotoxin D to the T cell receptor Vbeta chain and major histocompatibility complex class II

In an attempt to define the binding of staphylococcal enterotoxin D (SED) to the T cell receptor Vbeta (TCR Vbeta) and major histocompatibility complex (MHC) class II molecules, site-directed mutagenesis has been used to introduce alanine substitutions at Asn23, Phe45, Leu59, Asn61, Ile92 and Phe203 in SED. SED-N23A (SEA with Asn23 replaced with alanine) and SED-F45A mutants exhibit a significantly reduced ability to induce T cell proliferation. However, SED-L59A, SED-N61A, SED-I92A and SED-F203A mutants exhibit the normal mitogenic activity. The ability binding to MHC class II and the TCR Vbeta specificity of SED-N23A and SED-F45A were then detected. SED-N23A, but not SED-F45A, was able to compete effectively with FITC-conjugated SED for binding to Raji cells. This finding indicates that the mitogenic activity defection of SED-N23A is not due to poor binding to SED-MHC class II molecules. When stimulated with SED-N23A, T cells bearing TCR Vbeta5 were significantly reduced. When stimulated with SED-F45A, T cells bearing TCR Vbeta5, TCR Vbeta8 and TCR Vbeta12.1 were all significantly reduced. These results suggest Asn23 is an important residue involved SED interacting with TCR Vbeta; Phe45 is required for effective interaction with MHC class II molecules; and the ability of SED stimulating certain TCR Vbeta+ T cells is dependent on Phe45 binding to MHC class II molecules.     

Influence of different mechanical stimuli in a multi-scale mechanobiological isotropic model for bone remodelling

This work represents a study of a mathematical model that describes the biological response to different mechanical stimuli in a cellular dynamics model for bone remodelling. The biological system discussed herein consists of three specialised cellular types, responsive osteoblasts, active osteoblasts and osteoclasts, three types of signalling molecules, transforming growth factor beta (TGF-β), receptor activator of nuclear factor kappa-b ligand (RANKL) and osteoprotegerin (OPG) and the parathyroid hormone (PTH). Three proposals for mechanical stimuli were tested: strain energy density (SED), hydrostatic and deviatoric parts of SED. The model was tested in a two-dimensional geometry of a standard human femur. The spatial discretization was performed by the finite element method while the temporal evolution of the variables was calculated by the 4th order Runge–Kutta method. The obtained results represent the temporal evolution of the apparent density distribution and the mean apparent density and thickness for the cortical bone after 600 days of remodelling simulation. The main contributions of this paper are the coupling of mechanical and biological models and the exploration of how the different mechanical stimuli affect the cellular activity in different types of physical activities. The results revealed that hydrostatic SED stimulus was able to form more cortical bone than deviatoric SED and total SED stimuli. The computational model confirms how different mechanical stimuli can impact in the balance of bone homeostasis.     

Prediction of stress shielding around an orthopedic screw: Using stress and strain energy density as mechanical stimuli

Using finite element analysis, a parametric study was developed to compare stress and strain energy density (SED), in order to determine which stimuli might be better for predicting stress shielding in bone–screw models. Defined stimuli transfer parameters demonstrated that stress and SED (strong candidates for initiating the bone remodeling process) are transferred distinctively between an implant and bone. While small diameter angled threads increased transfer of both stimuli, reducing the screw's elastic modulus resulted in an increased transfer of stress; and unexpected decrease in SED, indicating that SED should be carefully examined in the context of future bone–screw models.     

Emotional Security With Teachers and Children's Stress Reactivity: A Comparison of Special-Education and Regular-Education Classrooms

Examined children's exposure and reactivity to negative peer and teacher events in special-education and regular-education classrooms. Participants were 40 children in regular classrooms and 20 children classified as seriously emotionally disturbed (SED) in special-education classrooms. Children completed 7 days of diary data over the course of the school year. SED children reported higher rates of exposure to negative teacher and peer events than comparison children. The self-esteem of both SED and comparison children was reactive to negative peer events in the classroom, but emotional security with teacher (EST) reduced this reactivity. The self-esteem of SED children was also reactive to negative teacher events but, EST, once again, reduced reactivity to negative events. Finally, SED children's perception of maternal warmth moderated their self-esteem reactivity and was concordant with their views of teachers. Results are discussed in light of treatment implications for SED children.     

A new type of autosomal recessive spondyloepiphyseal dysplasia tarda

Repeated occurrence of a hitherto unrecognized form of spondyloepiphyseal dysplasia tarda (SED tarda) has been studied in two independent families. Because parental consanguinity was also present in one family, autosomal recessive inheritance is proposed. The onset was in late childhood. The slowly evolving disorder shared several features of the already known types of SED tarda. The radiographic abnormalities were limited to the spine and proximal femora. The patients' hands were normal. The entity described is set apart not only from the X-linked and autosomal-dominant forms of SED tarda but also from the already delineated autosomal recessive types by significant clinical and radiographic differences. Final genotypic characterization must await the results of genetic linkage studies and of appropriate molecular genetics investigations.     

原核表达的葡萄球菌D型肠毒素超抗原的纯化及其促淋巴细胞增殖作用

目的　纯化原核表达的葡萄球菌D型肠毒素 (StaphylococcalenterotoxinD ,SED) ,检测其促淋巴细胞增殖活性 ,为SED免疫识别研究奠定基础。方法　用Ni2 + NTA金属螯合亲和层析法纯化 6×His SED融合蛋白 ,SDS PAGE和毛细管电泳检测蛋白纯度 ,BCA法进行定量 ,以3H TdR掺入法检测纯化的SED对人和小鼠淋巴细胞的促增殖活性。结果　获得可满足后续功能实验纯度较高的蛋白质 ;SED对人淋巴细胞的促增殖作用呈质量浓度依赖关系 ,0 .1μg mL时 ,细胞增殖最明显 ;淋巴细胞的增殖与IL 2分泌水平呈正相关。结论　原核表达的SED具有促人和小鼠淋巴细胞增殖活性     

Sustained rise in triacylglycerol synthesis and increased epididymal fat mass when rats cease voluntary wheel running

Four-week-old, Fischer–Brown Norway F1-generation male rats were given access to voluntary running wheels for 21 days, and then the wheels were locked for 5 (WL5), 10 (WL10), 29 (WL29), or 53 (WL53) hours. Two other groups (SED5 and SED10) had no access to voluntary running wheels and were killed at the same time as WL5 and WL10, respectively. Absolute and relative epididymal fat mass, mean cell volume, and amount of lipid per cell increased in WL53 relative to all other groups, with no change in cell number. C/EBPα protein levels in epididymal fat were 30% greater in SED5 than in WL5. The rate of triacylglycerol synthesis in epididymal fat was 4.2-fold greater in SED5 than in WL5, increased 14-fold between WLS and WL10, and was 79% lower in SED10 than in WL10. Triacylglycerol synthesis remained at this elevated level (at least 3.5-fold greater than SED5) through WL53. Thus, the rapid increase in epididymal fat mass with the cessation of voluntary wheel running is associated with a prolonged overshoot in epididymal fat triacylglycerol synthesis. Moreover, rats without running wheels had a 9.4% lower body mass after 21 days than those with running wheels. The individual mass of seven different muscles from the hindlimb, upper forelimb, and back were each lower in animals without running wheels, suggesting that physical activity in rapidly growing rats may be requisite for optimal muscle development.     

The phenotypic spectrum of COL2A1 mutations

Heterozygous mutations of COL2A1 create several clinical entities collectively termed type II collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-I), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1(II) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD-I to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype-phenotype relationship of type II collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in-frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice-site mutations in the triple helical or N-propeptide region caused STD-I or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes.     

Arterial blood pressure and forearm vascular conductance responses to sustained and rhythmic isometric exercise and arterial occlusion in trained rock climbers and untrained sedentary subjects

Cardiovascular responses to sustained and rhythmic (5?s on, 2?s off?) forearm isometric exercise to fatigue at 40% maximal voluntary contraction (MVC) and to a period of arterial occlusion were investigated in elite rock climbers (CLIMB) as a trained population compared to non-climbing sedentary subjects (SED). Blood pressure (BP), monitored continuously by Finapres, and forearm blood flow, by venous occlusion plethysmography, were measured and used to calculate vascular conductance. During sustained exercise, times to fatigue were not different between CLIMB and SED. However, peak increases in systolic (S) BP were significantly lower in CLIMB [25 (13)?mmHg; (3.3 (1.7)?kPa] than in SED [48 (17)?mmHg; (6.4 (2.3)?kPa] (P<0.05), with a similar trend for increases in diastolic (D) BP. Immediately after sustained exercise, forearm conductance was higher in CLIMB than SED (P<0.05) for up to 2?min. During rhythmic exercise, times to fatigue were two fold longer in CLIMB than SED [853 (76) vs 420 (69)?s, P<0.05]. Increases in SBP were not different between groups except during the last quarter of exercise when they fell in CLIMB. Conductance both during and after rhythmic exercise was higher in CLIMB than in SED. Following a 10-min arterial occlusion, peak vascular conductance was significantly greater in CLIMB than SED [0.597 (0.084) vs 0.431 (0.035)?ml · min^?1?· 100?ml^?1?·?mmHg^?1; P<0.05]. The attenuated BP response to sustained isometric exercise could be due in part to enhanced forearm vasodilatory capacity, which also supports greater endurance during rhythmic exercise by permitting greater functional hyperaemia in between contraction phases. Such adaptations would all facilitate the ability of rock climbers to perform their task of making repetitive sustained contractions.     

Exercise improves biomarkers of health and stress in animals fed ad libitum

Voluntary and forced exercise decrease morbidity and mortality in laboratory animals. Caloric restriction has similar effects on health and unique benefits on life span. Nonetheless, in most experiments, animals do not have access to physical activity and are fed ad libitum (AL). We hypothesized that with regular access to either unlimited running wheel exercise (EX) or limited physical activity (PA), key biomarkers of health would be enhanced enough to counter some consequences of a sedentary AL lifestyle. This 16-month study compared body weight, tumor number and size, tissue lesions, oxidative stress, and reactive stress in (1) sedentary animals with no access to physical activity (SED); (2) animals with access to hour-long, twice weekly activity in a large box (PA); and (3) animals with access every other day to a running wheel (EX). At the end of the study, EX body weight was 8-9% lower than PA and SED. In addition, EX had no kidney lesions versus 50% in PA and SED, and had smaller tumor size (10+/-2 vs. 14+/-4 and 30+/-4 mm). Exhaustive exercise lowered glutathione/oxidized glutathione ratio in EX and PA, but in SED, the ratio was depressed even in resting animals. In all treatments, prolactin (PRL) levels were lower in resting animals than in acutely exercised animals. In conclusion, EX had the most favorable health biomarkers while SED had the least. PA did not confer gross health benefits different than the SED group, but was biochemically more similar to EX animals.     

Staphylococcus aureus enterotoxin D is secreted in milk and stimulates specific antibody responses in cows in the course of experimental intramammary infection

An enterotoxin D (SED)-producing strain of Staphylococcus aureus was used to infect one mammary gland of each of 17 lactating dairy cows. All glands became infected and shed bacteria over a sampling period of 3 weeks. Serum and milk antibodies specific for SED were monitored by an enzyme-linked immunosorbent assay for 12 weeks. Elevated anti-SED antibodies were detected in all cows after infection, and immunoglobulin of the G2 subclass comprised most of the specific serum response. SED was detected in mastitic milk samples from two cows at levels of 5 to 10 ng/ml. An in vitro lymphocyte proliferation assay showed that SED at levels below 10 pg/ml induced proliferation of bovine lymphocytes and that sheep antiserum specific for SED neutralized this proliferative response. Sera obtained from the cows pre- and postinfection inhibited lymphocyte proliferation at SED concentrations of 10 and 50 ng/ml, respectively. The addition of SED to whole blood or to isolated neutrophils had no significant effect on neutrophil function in vitro. The results show that SED is secreted during mammary gland infection, is mitogenic for bovine lymphocytes, and stimulates the production of specific antibodies.     

Relationship between two aspects of self-oriented perfectionism and self-evaluative depression: using coping styles of uncontrollable events as mediators

Self-oriented perfectionism has two aspects: pursuing perfection simply as a goal (Personal Standard: PS) and not accepting imperfection (Concern for Mistake: CM, Doubting of Action: D). The former is said to enhance mental health, while the latter deteriorates it. The latter aspect may also have vulnerability to uncontrollable events. The present study used causal modeling to investigate the relation of these two aspects, self-evaluative depression (composed of Self-Esteem and Depression: SED), and styles of coping with uncontrollable events. A questionnaire measuring these concepts was completed by 169 college students, and the following results were yielded: Of the two aspects of self-oriented perfectionism, PS lowered SED, while CM and D heightened SED. PS increased such coping styles that attempt to control uncontrollable events as "Face and Act", "Positive expectation" and "Rumination", whereas CM increased "Avoidance", "Negative expectation" and "Self-blame" copings, which represent vulnerability to uncontrollable events. Moreover, Self-blame coping increased SED. These results suggested that CM was related, via Self-blame, to negative evaluation of imperfect self.     

Reported frequency of physical activity,fitness, and fatness in Kuwait

We studied reported frequency of physical activity (PA), body composition, and fitness in Kuwaiti females (n = 84) and males (n = 72), urban office government employees, or students. A sedentary (SED) group reported no or occasional participation in self‐directed PA of 30 minutes or more during the week for the last 6 months; group LOF (low frequency) participated in 1–2 sessions/week (walking, jogging, sports such as volleyball, soccer, or gym); group HIF (higher frequency) reported three or more sessions/week. Aerobic fitness was measured using Bruce's treadmill protocol. Body fat and fat‐free mass (FFM) were estimated from seven skinfolds and body weight (BW). Grip strength and trunk flexibility were also measured. Maximal O₂ consumption (VO₂max)/BW was proportional to reported frequency of PA in males and females, indicating reliability of the reported PA frequencies. SED males (%fat > 25), SED and LOF females (%fat > 30) were overweight. In males, LOF PA was associated with lower %fat and higher flexibility than SED, and in females with higher VO₂max/FFM than SED. LOF females, in contrast to males, were resilient to or exercised at levels insufficient for fat loss but sufficient for aerobic conditioning of the FFM, likely related to the low VO₂max of females in which PA would have the most effect. HIF PA (≥3/week) was associated in females with significantly lower %fat and higher flexibility than SED females and no further aerobic conditioning of the FFM, and in males with no further differences in study variables compared with LOF males. Grip strength was higher in males than females but was unrelated to frequency of PA, likely reflecting lack of strength training in the activities of most participants. Thus, low‐frequency PA was associated with health benefits both in males (lower %fat) and females (higher VO₂max/FFM). Probably due to the generally low fitness level of females and, hence, the high aerobic effort (%VO₂max) required for exercise sufficient to impinge on fat stores, this was only achieved in females participating in higher weekly frequency (≥3) of PA. Am. J. Hum. Biol. 15:514–521, 2003. © 2003 Wiley‐Liss, Inc.